Certain amino acids such as L-glutamic acid and L-aspartic acid are known to be central neurotransmitters. It is said that accumulation of these excitatory amino acids results in a persistent overstimulation of the nerves which, in turn, causes neuronal degeneration and mental and motor dysfunctions as are observed in Huntington's chorea, Parkinson's disease, epilepsy and senile dementia, or after cerebral ischemia, oxygen deficiency or hypoglycemia.
Therefore, it is by now considered that drugs which may modulate abnormal actions of these excitatory amino acids are useful for the treatment of neuronal degeneration and mental disease.
Excitatory amino acids exert their effects via the specific receptors present in the post- or presynaptic regions. These receptors have been classified into the following five groups based on electrophysiological and neurochemical evidence.
1) NMDA (N-methyl-D-aspartate) receptor
2) AMPA [2-amino-3-(3-hydroxy-5-methyl-4-isoxazole)-propionic acid] receptor
3) Kainate receptor
4) Metabotropic glutamate receptor
5) AP-4 (2-amino-4-phosphobutanoic acid) receptor
L-Glutamic acid and L-aspartic acid activate the above-mentioned receptors to transmit stimuli. Permitting an excessive amount of NMDA, AMPA or kainate to act on nerves causes neuropathy. It is reported that 2-amino-5-phosphonovalerianic acid and 2-amino-7-phosphonoheptanoic acid, both of which are selective antagonists of NMDA receptor, were effective in NMDA-induced neuropathy and in animal models of epilepsy or brain ischemia (JPET, 250, 100 (1989); JPET, 240, 737 (1987); Science, 226, 850 (1984)).
While NMDA receptor is reported to be allosterically functioning by glycine receptor (EJP, 126, 303 (1986)), HA-966 which is a glycine receptor antagonist is reported to be effective in an animal model of brain ischemia (1989 Congress of American Society of Neuroscientists).
NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline), a selective antagonist of AMPA receptor, is also reported to be effective in an animal model of brain ischemia (Science, 247, 571 (1990)). On the other hand, there is no report with respect to selective antagonists of kainate, metabotropic glutamate and AP-4 receptors.